This invention relates to intermediates useful in the preparation of prostaglandin analogs and to a process for preparing them.
Each of the known prostaglandins is a derivative of prostanoic acid which has the following structure and atom numbering: ##STR2## A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]heptanoic acid.
Prostaglandin E.sub.1, "PGE.sub.1 ", has the following structure: ##STR3##
Prostaglandin F.sub.1.sub..alpha., "PGF.sub.1.sub..alpha. ", has the following structure: ##STR4##
The prostaglandin formulas mentioned above each have several centers of asymmetry. Each formula represents a molecule of the particular optically active form of the prostaglandin obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, and human seminal plasma, or by reduction or dehydration of a prostaglandin so obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. The mirror image of each formula represents a molecule of the other enantiomeric form of that prostaglandin. The racemic form of the prostaglandins consists of equal numbers of two types of molecules, one represented by one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin. See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.
In the formulas above, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, e.e., above the plane of the cyclopentane ring. In the formulas above, the hydroxyl attachment to carbon 15 is in the alpha configuration, as indicated by the broken line. In formulas below, this convention is also used for intermediates having hydroxyl substituted at the corresponding position on the side chain. A wavy line .about. indicates attachment to the side chain in alpha or beta configuration.
The various optically active and racemic prostaglandins and their alkyl esters are useful for various pharmacological purposes. With particular regard to PGF.sub.1.sub..alpha. see, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. As to the other prostaglandins, see, for example, Ramwell et al., Nature 221, 1251 (1969).
Previously, certain prostaglandin analogs having an oxa oxygen (--O--) and a divalent phenylene moiety ##STR5## in the carboxyl-terminated side chain of the prostanoic acid structure (I) were disclosed. See German Offenlegungsschrift No. 2,209,990, Derwent Farmdoc No. 66,750T.
Included among those phenylene-oxa prostaglandin analogs were compounds represented by the formulas: ##STR6## and the racemic mixtures of those compounds and their respective enantiomers represented by the mirror images of the above formulas. The terms C.sub.p H.sub.2p, C.sub.t H.sub.2t, R.sub.1, R.sub.2, and R.sub.3, T, and s will be defined and illustrated below.
For example, specific compounds among the above phenyleneoxa prostaglandin analogs are represented by the following formulas by way of illustration: ##STR7## Based on its relationship to PGE.sub.1 and prostanoic acid, the compound of formula XII is named 3-oxa-4,7-inter-m-phenylene-5,6-dinor-PGE.sub.1. Similarly, the compound of formula XIII is named 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1.sub..alpha., methyl ester and the compound of formula XIV is named 3-oxa-3,7-inter-p-phenylene-15(R)-15-methyl-17-phenyl-4,5,6,18,19,-20-hexa nor-PGE.sub.1.
These names for the compounds of formulas XII, XIII, and XIV are typical of the names of the phenylene-oxa prostaglandin analogs produced by the intermediates obtained by the novel process herein. These names are based on the structure and numbering system of prostanoic acid (formula 1, above). That formula has 7 carbon atoms in the carboxy-terminated chain and 8 carbon atoms in the hydroxy-containing chain. In these names, "3-oxa" indicates an oxa oxygen (--O--) in place of the C-3 methylene of the prostaglandin (PG) compound.
The use of "nor", "dinor", "trinor", "tetranor", "pentanor", "hexanor", and the like in the names for the PG analogs referred to herein indicates the absence of one or more of the chain carbon atoms and the attached hydrogen atoms. The number or numbers preceding nor, dinor, etc., indicate which of the original prostanoic acid carbon atoms are missing in the named compound.
Each of the names of the PG analogs referred to herein contains (inter-p-phenylene), (inter-m-phenylene), or (inter-o-phenylene), preceded by two numbers. That indicates that p-phenylene, m-phenylene, or o-phenylene has been inserted between (inter) the two carbon atoms so numbered in the formula of prostanoic acid.
Thus, formula XII differs from PGE.sub.1 and prostanoic acid in that an oxa oxygen replaces carbon 3, carbons 5 and 6 are missing, and m-phenylene is inserted between carbons 4 and 7.
Included in the above analogs are those with epi configuration for the hydroxy at C-15, illustrated by formula XIV. Where the C-15 configuration is the same as that of the natural prostaglandin PGE.sub.1, identifies as "S" configuration, the name ordinarily does not identify the configuration at C-15 unless there is 15-alkyl substitution. If the 15-epimer is intended, the name usually includes "15(R)" or "15-beta". See R. S. Cahn, Journal of Chemical Education 41, 116 (1964) for a discussion of S and R configurations.
Formulas IV, VI, VIII, and X as printed represent optically active prostaglandin analogs with the same absolute configuration as PGE.sub.1 or PGF.sub.1.sub..alpha. obtained from mammalian tissues. Formulas V, VII, IX, and XI represent their respective 15-epimers. Each of formulas IV-XI plus its mirror image describes a racemic mixture designated herein by the prefix "racemic" or "dl" before its name. When that prefix is absent, the intent is to designate an optically active compound represented by the appropriate formula.
In formulas IV-XI and wherever used in this disclosure, the term C.sub.n H.sub.2n represents alkylene of one to 4 carbon atoms, inclusive; C.sub.p H.sub.2p represents a valence bond or alkylene of one to 4 carbon atoms, inclusive, with one or 2 carbon atoms in the chain between the phenyl ring and --C--. C.sub.t H.sub.2t represents a valence bond or alkylene of one to 10 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, and, when C.sub.t H.sub.2t is alkylene, having one to 7 carbon atoms, inclusive, in the chain between --CR.sub.3 -- and the phenyl rings R.sub.1 is hydrogen or alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; R.sub.2 is alkyl of 2 to 10 carbon atoms, inclusive, substituted with zero, one, 2, or 3 fluoro; R.sub.3 is hydrogen or alkyl of one to 4 carbon atoms, inclusive; T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or OR.sub.17, wherein R.sub.17 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein s is zero, one, 2, or 3 with the proviso that not more than two T's are other than alkyl.
Each of the phenylene-oxa prostaglandin analogs represented by formula IV-XI is useful in place of the corresponding known prostaglandins for at least one of their known pharmacological purposes, which include reduction of gastric secretion, inhibition of blood platelet aggregation, increase of nasal patency, and labor inducement at term.